Submissions for variant NM_006767.4(LZTR1):c.2368C>T (p.Arg790Trp)

gnomAD frequency: 0.00002  dbSNP: rs767637944

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001317211	SCV001507862	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 790 of the LZTR1 protein (p.Arg790Trp). This variant is present in population databases (rs767637944, gnomAD 0.004%). This missense change has been observed in individual(s) with autism spectrum disorder (PMID: 28191889). ClinVar contains an entry for this variant (Variation ID: 1017977). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LZTR1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001317211	SCV001991010	uncertain significance	not provided	2024-03-28	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with autism spectrum disorder (PMID: 28191889); This variant is associated with the following publications: (PMID: 28191889)
Institute of Human Genetics, University Hospital Muenster	RCV004584435	SCV002577794	uncertain significance	See cases	2021-12-16	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PP3
Ambry Genetics	RCV002447345	SCV002735002	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-03-30	criteria provided, single submitter	clinical testing	The p.R790W variant (also known as c.2368C>T), located in coding exon 20 of the LZTR1 gene, results from a C to T substitution at nucleotide position 2368. The arginine at codon 790 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV004570756	SCV005060676	uncertain significance	Schwannomatosis 2	2023-12-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699303	SCV005204749	uncertain significance	not specified	2024-06-27	criteria provided, single submitter	clinical testing	Variant summary: LZTR1 c.2368C>T (p.Arg790Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250638 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2368C>T has been reported in the literature in an individual affected with a neurodevelopmental disorder without clinical information (Stessman_2017). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28191889). ClinVar contains an entry for this variant (Variation ID: 1017977). Based on the evidence outlined above, the variant was classified as uncertain significance.